Polyester implantable medical device with controlled in vivo biodegradability

ABSTRACT

This invention relates to blends of high, optionally medium, and low molecular weight polyesters where at least the low molecular weight polyester is substituted with an acidic moiety, the biodegradation of the blends being controllable by selection of the mean molecular weigh of each fraction, the quantity of each fraction in the blend and the amount and pKa of the acidic moiety(ies).

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a continuation application of U.S. application Ser.No. 12/165,092 filed on Jun. 30, 2008, the teaching of which isincorporated by reference in its entirety herein.

FIELD

This invention relates to organic chemistry, polymer chemistry, materialscience and medical device technology. In particular it relates topolyester implantable medical devices with controllable in vivobiodegradation properties.

BACKGROUND

Until the mid-1980s, the accepted treatment for atherosclerosis, i.e.,narrowing of the coronary artery(ies) was by-pass surgery. Whileeffective and while having evolved to a relatively high degree of safetyfor such an invasive procedure, by-pass surgery still involvespotentially serious complications and in the best of cases an extendedrecovery period.

With the advent of percutaneous transluminal coronary angioplasty (PTCA)in 1977, the scene changed dramatically. Using catheter techniquesoriginally developed for heart exploration, inflatable balloons wereemployed to re-open occluded regions in arteries. The procedure wasrelatively non-invasive, took a very short time compared to by-passsurgery and the recovery time was minimal. However, PTCA brought with itother problems such as vasospasm and elastic recoil of the stretchedarterial wall which could undo much of what was accomplished and, inaddition, it created a new disease, restenosis, the re-clogging of thetreated artery due to neointimal hyperplasia.

The next improvement, advanced in the mid-1980s was the use of a stentto maintain the luminal diameter after PTCA. This for all intents andpurposes put an end to vasospasm and elastic recoil but did not entirelyresolve the issue of restenosis. That is, prior to the introduction ofstents, restenosis occurred in from 30-50% of patients undergoing PTCA.Stenting reduced this to about 15-20%, much improved but still more thandesirable.

In 2003, drug-eluting stents or DESs were introduced. The drugsinitially employed with the DES were cytostatic compounds, that is,compounds that curtailed the proliferation of cells that resulted inrestenosis. The occurrence of restenosis was thereby reduced to about5-7%, a relatively acceptable figure. However, the use of DESsengendered a new problem, late stent thrombosis, the forming of bloodclots long after the stent was in place. It was hypothesized that theformation of blood clots was most likely due to delayed healing, aside-effect of the use of cytostatic drugs.

Generally speaking, stents achieve their optimal beneficial effectwithin 24 months of implantation and sometimes substantially less.Because of the materials of which stents are constructed, however, theytend to have much longer in vivo life spans, which tends to contributeto late stent thrombosis. This is of course true of very biostablemetallic stents but it holds as well for most polymeric stents. Whilepolymers that biodegrade relatively rapidly, easily in 24 months orless, are known, they generally do not exhibit the physical propertiesrequired of stents like strength, toughness, ductility and the like,while polymers that do exhibit these characteristics tend to have muchlonger biodegradation times.

What is needed is a polymeric implantable medical device that exhibitsall the physical characteristics desired in such devices while alsobeing essentially fully biodegradable over a clinically relevanttimeframe. The present invention provides such implantable devices.

SUMMARY

Thus, in one aspect the invention relates to an implantable medicaldevice, comprising:

-   a blend of a high molecular weight polyester and a low molecular    weight polyester, wherein    -   the high molecular weight polyester has a molecular weight of        about 200,000 Da to about 1,000,000 Da;    -   the low molecular weight polyester has a molecular weight of        about 200 Da to about 20,000 Da;    -   the low molecular weight polyester comprises about 0.1% w/w to        about 5% w/w of the blend; and,    -   the low molecular weight polyester comprises an acidic moiety.

In an aspect of this invention, the acidic moiety is selected from thegroup consisting of a carboxylic acid, a sulfinic acid, a sulfonic acidand a phosphonic acid.

In an aspect of this invention, the acidic moiety is a carboxylic acid.

In an aspect of this invention, the high molecular weight polyestercomprises an acidic moiety.

In an aspect of this invention, the acidic moiety of the high molecularweight polyester is the same as the acidic moiety of the low molecularweight polyester.

In an aspect of this invention, the blend further comprises a mediummolecular weight polyester having a molecular weight of about 20,000 DAto about 200,000 Da.

In an aspect of this invention, the medium molecular weight polyestercomprises an acidic moiety selected from the group consisting of acarboxylic acid, a sulfinic acid, a sulfonic acid, a phosphonic acid andcombinations thereof.

In an aspect of this invention, the acidic moiety of the mediummolecular weight polyester is the same as the acidic moiety of the lowmolecular weight polyester.

In an aspect of this invention, the low molecular weight polyestercomprises from about 0.2% w/w to about 5% w/w of the blend.

In an aspect of this invention, the medium molecular weight polyestercomprises about 2% w/w to about 20% w/w of the blend.

In an aspect of this invention, the medium molecular weight polyestercomprises about 2% w/w to about 20% w/w of the blend.

In an aspect of this invention, the medium molecular weight polyestercomprises about 5% w/w to about 10% w/w of the blend.

In an aspect of this invention, the high molecular weight polyester hasa molecular weight from about 300,000 Da to about 700,000 Da.

In an aspect of this invention, the low molecular weight polyester has amolecular weight of about 500 Da to about 10,000 Da.

In an aspect of this invention, the medium molecular weight polyesterhas a molecular weight of about 50,000 Da to about 100,000 Da.

In an aspect of this invention, the high molecular weight polyester andthe low molecular weight polyester are independently selected from thegroup consisting of poly(L-lactide), poly(D-lactide),poly(L-lactide-co-ε-caprolactone), poly(D-lactide-co-ε-caprolactone),poly(L-lactide-co-trimethylene carbonate),poly(D-lactide-co-trimethylene carbonate) and combinations thereof.

In an aspect of this invention, the high molecular weight polyester andthe low molecular polyester are the same polyester.

In an aspect of this invention, the polyester is poly(L-lactide) orpoly(D-lactide).

In an aspect of this invention, the medium molecular weight polyester isthe same as the high molecular weight and the low molecular weightpolyester.

In an aspect of this invention, the high molecular weight polyester, themedium molecular weight polyester and the low molecular weight polyesterare all poly(L-lactide) or poly(D-lactide).

In an aspect of this invention, the implantable medical device comprisesstent.

In an aspect of this invention, the stent is a vascular stent.

In an aspect of this invention the vascular stent degrades substantiallycompletely in about 8 to about 24 months.

In an aspect of this invention, the stent biodegrades substantiallycompletely in about 10 to about 16 months.

In an aspect of this invention, the implantable medical device comprisesa nanoparticles or a microparticle.

In an aspect of this invention, the nanoparticles or microparticlecomprises a therapeutic agent encapsulated therein.

DETAILED DESCRIPTION

Use of the singular herein includes the plural and vice versa unlessexpressly stated or unambiguously obvious from the context to beotherwise. That is, “a” and “the” refer to one or more of whatever theword modifies. For example, “a carboxylic acid moiety” may refer to one,two, three or more such moieties. Likewise, “the medium molecular weightpolyester” may refer to one, two or more different medium molecularweight polyesters. By the same token, words such as, without limitation,“therapeutic agents” and “polymers” would refer to one therapeutic agentor one polymer as well as to a plurality of such agents or polymers,again, unless it is expressly stated or obvious from the context thatsuch is not intended.

As used herein, a condition or event modified by the words “substantial”or “substantially” means that, while not exactly what the condition orevent would be understood to be if unmodified, it would be consideredclose enough by those of ordinary skill in the art to warrantdesignating the condition or event as being extant. Thus, for thepurpose of this invention, an implantable medical device that is statedto “biodegrade substantially completely” over a given time period meansthat, while vestiges of the device may remain, those remnants do notexhibit any of the physical characteristics of the intact device and infact may not be located at exactly the same position in a patient's bodyas that to which it was initially deployed. Further, the remnants wouldbe of a size and quantity so as to not participate in the creation oflate-stent thromboses.

The use of other words or approximation herein, such as “about” or“approximately” when used to describe numerical values or rangeslikewise are understood to mean that those skilled in the art wouldreadily consider a value different from the exact number or outside theactual range to be close enough to come within the aegis of that numberor range. At the very least, “about” or approximately is understood tomean ±15% of a given numerical value or range starting and ending point.

As used herein, “optional” means that the element so-modified may or maynot be present.

As used herein, “biodegradable” refers to any natural means by which apolymer can be disposed of in a patient's body. This includes suchphenomena as biological decomposition, bioabsorption, resorption, etc.Biodegradation of a polymer in vivo results from the action of one ormore endogenous biological agents and/or conditions such as, withoutlimitation, enzymes, microbes, other cellular components, physiologicalpH and temperature and the like. Bioabsorbable or bioresorbable on theother hand generally refers to the situation wherein the polymer itselfor its degradation products are removed from the body by cellularactivity such as, without limitation, phagocytosis. Bioerodible refersto both physical processes such as, without limitation, dissolution andchemical processes such as, without limitation, backbone cleavage byhydrolysis of the bonds linking constitutional units of a polymertogether. As used herein, biodegradable includes bioerodible,bioresobable and bioabsorbable.

Biodegradable polymers are preferred for many applications because theirability to decompose in a biological environment confers on them anumber of desirable characteristics. For example, the fact that apolymer will biodegrade and can eventually be essentially completelyeliminated from a patient's body can avoid the need to invasively removea device, e.g., a DES, after its job is done. In addition, by judiciouschoice of biodegradable polymer, e.g., selecting one that bioerodes bybulk erosion, one that bioerodes by surface erosion or some combinationthereof, the properties of the polymer can be used as an added tool forfine-tuning the release rate of a drug from a device or a coating on adevice.

Of course, if a polymer is going to degrade in a patient's body, it isimperative that it be biocompatible, that is, that its degradationproducts do no harm to the patient. As used herein, “biocompatible”refers to a polymer that both in its intact, as initially synthesizedand deployed, state, and its biodegradation products, are not, or atleast are minimally, toxic to living tissue; do not, or at leastminimally and reparably, injure(s) living tissue; and/or do not, or atleast minimally and/or controllably, cause(s) an immunological reactionin living tissue. To achieve this characteristic requires carefulattention to the chemistry of the polymer and its degradation products.A great deal of work has gone into the effort to find suitablebiodegradable polymers and one class of such polymers that has exhibitedparticularly desirable properties in terms of biocompatibility andbiodegradation as well as other physical characteristics that can beengineered into the polymer by judicious selection their constitutionalunits are polyesters.

As used herein, “polyester” refers to a polymer that has as itspredominant main chain or “backbone” structural characteristic an ester,—C(O)O—, moiety. Thus the generic structure of a polyester can bedepicted in the following manner: —[RC(O)ORC(O)O]_(n)—, wherein Rcomprises a hydrocarbon entity such as alkyl, cycloalkyl, alkenyl,alkynyl and aryl groups, any of which may be further substituted withone or more functional groups. For the purposes of this invention,polyesters also includes polycarbonates, i.e., the above structurewherein R is —R′O—, that is the generic structure becomes:

-   —[R′OC(O)OR′OC(O)O]_(n)—, and polythioesters in which one or more of    the oxygen atoms of the ester or carbonate moiety is replaced by    sulfur.

A polymer of this invention may be a homopolymer, a copolymer, a starpolymer, a dendritic polymer (dendrite) or a graft polymer, althoughpresently preferred are homopolymers and copolymers.

A homopolymer simply refers to a polymer comprising a single monomer, amonomer simply being a molecule that is iteratively reacted with itselfto form chains of constitutional units, i.e., a polymer. A copolymerrefers to a polymer prepared from two or more monomers that may bereacted so as to form random copolymers, regular alternating copolymers,random alternating copolymers, regular block copolymers or random blockcopolymers. A random copolymer has the general structure, assuming threemonomers/constitutional units, x-x-y-x-z-y-y-x-z-y-z- . . . , while aregular alternating copolymer has the general structure: . . .x-y-z-x-y-z-x-y-z- . . . and a random alternating copolymer has thegeneral structure: . . . x-y-x-z-x-y-z-y-z-x-y- . . . , it beingunderstood that the juxtaposition of constitutional units shown here isfor purpose of illustration only and a copolymer of this invention mayvary from that shown. A regular block copolymer has the generalstructure: . . . x-x-x-y-y-y-z-z-z-x-x-x . . . , while a random blockcopolymer has the general structure: . . .x-x-x-z-z-x-x-y-y-y-y-z-z-z-x-x-z-z-z- . . . . Similarly to random andregular and alternating copolymers, the juxtaposition of blocks, thenumber of constitutional units in each block and the number of blocks ina block copolymer of this invention are not in any manner limited by thepreceding illustrative generic structures. In fact, presently preferredpolymers of this invention are either homopolymers or two-monomercopolymers but the general principles above still pertain.

Presently preferred polyesters include poly(l-lactide), poly(d-lactide),poly(l-lactide-co-ε-caprolactone), poly(d-lactide-co-ε-caprolactone),poly(l-lactide-co-trimethylene carbonate) andpoly(d-lactide-co-trimethylene carbonate).

A “star” polymer refers to the product of the reaction of a smallmultifunctional core molecule with one or more difunctional molecules tocreate a branched configuration:

A dendritic polymer refers to a star-like polymer in which theconsititutional units emanating from the core structure are themselvesmultifunctional (3 or more functional groups) such that branchingcontinues throughout the polymerization process. That is, a dendriticpolymer can be schematically represented as:

wherein each level of branching is called a “generation.” That is, theschematic dendrite shown above would be considered a third generationdendrite.

Of course, the use of the cyclopropane core unit which results in threebranches initially for the illustrative star polymer and dendrimer aboveis non-limiting; the core unit may be more or less branches and need notbe cyclic; neither star polymers nor dendrimers are so limited.

A graft polymer simply refers to a macromolecule to which additionalpolymeric moieties are attached to a main backbone structure as sidechains, the side chains generally having constitutional orconfigurational features that differ from those of the main chain:

wherein the sequence of “B” groups constitutes the main or backbonechain and the “S” groups constitute the side chain or grafted entity.

As used herein a “constitutional unit” refers to the repeating structurein a polymer backbone, the constitutional unit resulting from thereaction of monomers. For example, without limitation, apoly(l-lactide), which is a presently preferred polymer of thisinvention, is prepared by the polymerization of the monomer l-lactide:

while the constitutional unit derived therefrom is

A polyester of this invention may be high, medium or low molecularweight. The terms “high,” medium” and “low” are intended to be relativeterms. That is, a polyester of arbitrary molecular weight 150,000 Da mayconstitute any of the three levels of molecular weight polymers. Forexample, if the 150,000 Da polyester is paired with two other polyestersof molecular weight 200,000 Da and 300,000 Da, then it would obviouslybe the “low” molecular weight polyester. If, on the other hand, it wereto be paired with a 125,000 Da and a 20,000 Da polyester, it wouldcomprise the “high” molecular weight polyester and so on.

It is presently preferred that the molecular weight of polymers of thisinvention be reported as the so-called “number average molecularweight,” which is calculated by dividing the weight of a sample ofpolymer by the total number of polymer molecules making up that sample.

The molecular weight may, however, be determined as a “weight averagemolecular weight” so long as the molecular weight of all polymerfractions are determined by the same method. The weight averagemolecular weight is determined by dividing the total number of polymermolecules times the weight of each molecule squared by the total numberof molecules times the weight of each molecule.

Seeing as the weight average molecular weight is proportional to thesquare of the individual molecular weights, it is always greater thanthe number average molecular weight. If the weight average molecularweight is divided by the number average molecular weight for any polymerfraction, a number referred to as the polydispersity index, PI, isobtained. The PI is a measure of the range of individual molecularweights that averages out to give the stated mean molecular weight. Asthe weight average molecular weight approaches the number averagemolecular weight, the PI approaches 1, 1 being indicative of a perfectlymonodisperse polymer in which each molecule has exactly the samemolecular weight. For the purposes of this invention, the PI may varyfrom close to 1 to virtually as high as can be achieved.

For the purposes of this invention, a high molecular weight polyester ofhas a number average molecular weight of about 200,000 Da to about1,000,000 Da, preferably at present about 300,000 Da to about 700,000Da. A medium molecular weigh polyester of this invention has a molecularweight of about 20,000 Da to about 200,000 Da, preferably at presentabout 50,000 Da to about 100,000 Da. A low molecular weight polyester ofthis invention has a molecular weight of about 200 Da to about 20,000Da, preferably at present about 500 Da to about 10,000 Da.

The high and low molecular weight polyesters are blended together toform a composition of this invention. By “blended” is simply meant thatthey are mixed together until a homogenous mass of material is obtainedwhereby a sample taken from any location in the final blend will havethe same percent low molecular weight polyester as a sample taken fromany other location in the blend. If a medium molecular weight polyesterin included in the blend, it also would be mixed with the high and lowmolecular weight polyesters until a sample taken at any location in theblend would have the same percent of low and medium weight polyester asa sample taken from any other location in the blend.

It is preferred that the weight percent (w/w) of low molecular weightpolyester in a blend of this invention be about 0.1% to about 5%,preferable at present, about 0.2% to about 2%.

If a medium molecular weight polyester is include in the blend, it ispreferred that its weight percent by about 2% to about 20%, preferablyat present about 5% to about 10%.

At least a portion of the low molecular weigh polyester of thisinvention is functionalized with an acidic moiety. By “at least aportion” is meant that at least 20% but a high as 100% of the lowmolecular weight polyester molecules must be substituted with at leastone acidic moiety. Preferably at present about 50% to about 100% are sofunctionalized. The percentage functionalization is readily obtainableby mixing 100% functionalized (or as close to 100% as is experimentallyattainable) polyester by weight with non-functionalized polyester toarrive at the desired percentage. For the purposes of this invention an“acidic moiety” is any group that exhibits a pKa below about 6, whichincludes, without limitation, carboxylic acids, —CRR′C(O)OH, sulfinicacids, —CRR′S(O)OH, sulfonic acids, CRR′S(O)₂OH and phosphonic acids,—CRR′P(O)₃OH. R and R′ are groups that modulate the pKa of the acidicmoiety such as, without limitation, halo (fluorine, chlorine, bromine,iodine), nitro (NO₂), alkyl and aryl groups. By judicious choice of Rand R′, the pKa and therefore the effect on the polyester of the acidicmoiety can be fine-tuned to a selected value. The effect of varioussubstituents on the pKa of an acidic moiety is well-known in the art andbased on the disclosures herein those skilled in the art will have notrouble manipulating the pKa of an acidic moiety of this invention toachieve whatever polyester degradation rate they desire.

The acidic moiety may be covalently bonded at any location along thebackbone of the polymer, either directly or through a linker group. A“linker” simply refers to any group that is covalently bonded to thebackbone of the polyester at one position and to an acid moiety (or anacidic moiety precursor) at a different position. For example, withoutlimitation, any of the following could be a “linker” for the purposes ofthis invention: —X(CH₂)_(n)C(O)OH, —XCH₂CH₂(OCH₂CH₂)_(n)CH₂CH₂C(O)OH,—XC(O)CH₂CH₂C(O)OH and

where X, through which the linker is bonded to the polymer backbone, canbe oxygen, nitrogen or sulfur.

Preferably at present the acidic moiety(ies) are located at the terminiof the polymer chains. It is well-known in the art how to preparepolyesters that have hydroxyl groups at either or both ends of theindividual chains, e.g., without limitation:RO—[C(O)CH(CH₃)O]_(n)C(O)CH(CH₃)OHwherein the R group may be a protective group that can be removed afterthe polymerization is complete to reveal a second hydroxyl group. Suchprotective groups are well known in the art and will not be furtherdiscussed here. The particular hydroxy-terminated polyester shown aboveis a hydroxy-terminated polylactide (PLA-OH), which, while a usefulpolymer of this invention, is not in any manner intended nor it is to beconstrued to limit the scope hereof. The conversion of thehydroxy-terminated polymer to a carboxy-terminated polymer can beaccomplished by any number of procedures such as, without limitation,reaction with succinic anhydride:

Those skilled in the art will envision other procedures for bonding acarboxyl group to the polymer backbone based on the discussion herein;all such procedures are within the scope of this invention.

Sulfinic, sulfonic and phosphonic acidic moieties may be formedsimilarly. For example, without limitation, benzene sulfinic, sulfonicand phosphonic acids are well-known in the art and in fact arecommercially available. These may be chloromethylated, for examplewithout limitation, by reaction with formaldehyde and hydrochloric acidand the chloromethylated derivative reacted with the hydroxyl end-groupsof the polyester to afford the desired acidic moiety-containingpolyester.

While at least a fraction of the low molecular weight polyester of ablend of this invention must include an acidic moiety, all or part ofthe high and medium molecular weight polyesters may independentlyoptionally also comprise an acidic moiety. In this regard, if the mediummolecular weight polyester does comprise an acidic moiety it ispreferred that about 20% to about 100%, preferably at present about 50%to about 100% of the medium molecular weight polyester be sofunctionalized.

With regard to the high molecular weight polyester, if it is optionallyfunctionalized with an acid moiety, it is preferred that about 20% toabout 100%, preferably about 50% to about 100% of the high molecularweight polyester be so functionalized.

Arriving at the desired percentage acidic moiety for medium and highmolecular weight polyesters is accomplished in the same manner as setforth about with regard to low molecular weight polyesters.

Further, if more than just the low molecular weight polyester fractionis substituted with an acidic moiety, the acidic moiety on the otherfractions may be the same as or different than the acidic moiety on thelow molecular weight fraction and the same as or different that theacidic moiety on each other.

The polyester blends of this invention may comprise one specificpolyester as the high and low or high, medium and low molecular weightpolymers; e.g., all might, without limitation, be poly(l-lactide)s. Orone or two of the polyesters may be of one sort while the third may beof another; e.g., without limitation, the high molecular weightpolyester may be poly(l-lactide), the medium molecular weight polyestermay be poly(l-lactide-co-trimethylene carbonate) and the low molecularweight polyester may be poly(trimethylene carbonate). Further, ifdesired each molecular weight level may comprise a mixture ofpolyesters; e.g., without limitation, the high and/or the medium, ifpresent, and/or the low molecular weight polyesters may be mixtures ofpoly(l-lactide) and poly(d-lactide) or, again without limitation,poly(l-lactide) and poly(trimethylene carbonate). All such mixtures andcombinations of polyesters are within the scope of this invention.

As used herein, an “implantable medical device” refers to any constructthat is totally or partly introduced, surgically or medically, into apatient's body or by medical intervention into a natural orifice, andwhich is intended to remain in place until the device biodegrades.

Examples of implantable medical devices are, without limitation, vesselwraps and stents. A vessel wrap is a thin sheet of flexible material,which may be fabric, polymer, metal, etc. that is literally wrappedaround the outside of a vessel and is in contact with the outer surface.The wrap may be solid or it may be formed in virtually any manner ofdesired pattern such as, without limitation, a mesh or a ribbedpolymeric structure.

As used herein, a “stent” refers generally to any device used to holdtissue in place in a patient's body. Particularly useful stents,however, are those used for the maintenance of the patency of a vesselin a patient's body when the vessel is narrowed or closed due todiseases including, without limitation, tumors (in, for example, bileducts, the esophagus, the trachea/bronchi, etc.), benign pancreaticdisease, coronary artery disease, carotid artery disease and peripheralarterial disease such as atherosclerosis, restenosis and vulnerableplaque. A stent can be used in, without limitation, neuro, carotid,coronary, pulmonary, aorta, renal, biliary, iliac, femoral and poplitealarteries as well as other peripheral vasculatures. A stent can be usedin the treatment or prevention of diseases such as, without limitation,thrombosis, restenosis, hemorrhage, vascular dissection or perforation,vascular aneurysm, chronic total occlusion, claudication, anastomoticproliferation, bile duct obstruction and ureter obstruction.

In addition to the above uses, stents, including those of thisinvention, may be employed for the delivery of therapeutic agents tospecific treatment sites in a patient's body. In fact, therapeutic agentdelivery may be the sole purpose of the stent or the stent may beprimarily intended for another use such as those discussed above withdrug delivery providing an ancillary benefit.

A further example of an implantable medical device of this invention isa nanoparticles or a microparticle in which is embedded a therapeuticagent intended to be released at a desired location in a patient's body.

As used herein, a “nanoparticle” refers to a solid having as its largestcross-sectional, i.e., through the solid as opposed to along itssurface, dimension of no greater than 100 nanometers. The solid can haveany desired shape although substantially spherical particles arewell-known in the art, are readily prepared and are presently preferred.By “substantially spherical” is meant that the particles need not have asurface that mimics a table tennis ball, i.e., virtually perfectlyspherical but rather may by odd-shaped but would be considered generally“round” by one of skill in the art.

A microparticle has the same characteristics as a nanoparticles exceptthat its smallest cross-sectional dimension is greater than 100 nm. Themaximum size of a microparticle will depend at least in part on theroute of administration, e.g., without limitation, oral, subcutaneousimplantation, catheter delivery, etc. and will be readily determinableby the skilled artisan

As used herein, “therapeutic agent” refers to any substance that, whenadministered in a therapeutically effective amount to a patientsuffering from a disease, has a therapeutic beneficial effect on thehealth and well-being of the patient. A therapeutic beneficial effect onthe health and well-being of a patient includes, but it not limited to:(1) curing the disease; (2) slowing the progress of the disease; (3)causing the disease to retrogress; or, (4) alleviating one or moresymptoms of the disease. As used herein, a therapeutic agent alsoincludes any substance that when administered to a patient, known orsuspected of being particularly susceptible to a disease, in aprophylactically effective amount, has a prophylactic beneficial effecton the health and well-being of the patient. A prophylactic beneficialeffect on the health and well-being of a patient includes, but is notlimited to: (1) preventing or delaying on-set of the disease in thefirst place; (2) maintaining a disease at a retrogressed level once suchlevel has been achieved by a therapeutically effective amount of asubstance, which may be the same as or different from the substance usedin a prophylactically effective amount; or, (3) preventing or delayingrecurrence of the disease after a course of treatment with atherapeutically effective amount of a substance, which may be the sameas or different from the substance used in a prophylactically effectiveamount, has concluded.

Based on the disclosure herein, those skilled in the art will be able tocombine the variables of this invention to achieve whateverbiodegradation rate they desire, the variables being the mean molecularweight of each fraction, the number of fractions, i.e., high and lowmolecular weight only or high, medium and low molecular weight, thequantity of each fraction in the blend, the pKa of the acidic moiety andthe quantity of acid moiety in the blend, e.g., all of the low molecularweight fraction or just a part of it, whether or not the high and/ormedium weight comprise acidic moieties and, if so, the quantity of suchacidic moieties in each fraction and the pKa of each of those moieties.

In general, as the pKa of the acidic moiety decreases, that is, as themoiety become more acidic, the rate of degradation of a polyester willincrease as it also will with increasing quantities of acid moiety.

Overall, the degradation time of pure high Mw PLLA is about 3 years ormore. The degradation time for a pure middle Mw PLLA with acidicmoieties would be less than 2 year, possibly less than 1 year dependingon the degree of incorporation of acidic moieties in the polymer. Thedegradation rate of a low Mw PLLA with acidic moieties would be lessthan 8 months and as low as 4 months or even less, again depending onthe degree of acid moiety substitution. Thus, in a non-limiting example,the degradation time of the same high Mw PLLA that in pure stateexhibits a degradation time of 3 years can be decreased to less than 1.5year or even less than 1 year with up to 5% low Mw PLLA having acidicmoieties. Based on the disclosures herein, those skilled in the artshould be able to create a polyester implantable medical device havingvirtually any degradation time by adjusting the molecular weights of thetwo (high and low) or three (high, medium and low) polyesters, thequantity of each in the blend used to make the device, the degree ofacidic moiety substitution and the pKa of the acidic moiety(ies).

EXAMPLES Example 1 Synthesis of PLLA-COOH

PLLA-COOH is synthesized in two steps. First, OH-terminated PLLA(PLLA-OH) is synthesized by the ring-opening polymerization of L-lactidein the presence of various kinds of alcohols. Then, PLLA-COOH isprepared through the acidification of PLLA-OH (see Scheme 1a and 1b).

1a. Synthesis of OH-Terminated Polylactide (PLLA-OH)

L-Lactide and 1-dodecanol are added in a glass ampoule containing aTeflon-coated magnetic stirring bar. After Sn-oct catalyst is added, theampoule is sealed under a vacuum after being purged three times withnitrogen at 90° C. The ampoule is heated to 130° C. in an oil bath for 5h with stirring. After the reaction, the product is dissolved inchloroform and micro-filtered through a 0.45-mm-pore membrane filter.The polymer is precipitated into methanol, filtered, and dried under avacuum. For the synthesis of the star-shaped PLLA-OH, the polymerizationis carried out with Sn-oct in the presence of glycerol orpentaerythritol.

1b. Synthesis of COOH-Terminated Polylactide (PLLA-COOH)

The PLLA-OH, succinic anhydride, 4-dimethylaminopyridine (DMAP), andtriethylamine (TEA) are dissolved in 1,4-dioxane and stirred overnightat room temperature. 1,4-Dioxane is re-moved under a vacuum, and theresidue is dissolved in chloroform and then washed with distilled waterthree times. After the chloroform layer separated, it is dried overanhydrous MgSO₄ and filtered. The polymer is precipitated into methanol,filtered, and dried under a vacuum.

Example 2 Bi-Modal PLLA-COOH System and Stent Preparation

2a. Preparation of Bi-Modal PLLA-COOH System

200 g medium Mw PLLA-COOH (Mw=100 kg/mol) is mixed with 1 kg high MwPLLA-COOH (Mw=600 kg/mol) at room temperature in a 2 L mechanicalblender with stirring speed at 300 rpm for 5-10 min. In order to achievethe best blending effect, a 2 L batch mixer or twin screw compounder canbe used to for the blending at 190° C.

2b. Tubing Extrusion

The bi-modal PLLA-COOH blend tubing is formed through extrusion in asignal or twin screw extruder at 200° C. The size of the extruded tubingis set at 0.02″ for ID and 0.06″ for OD.

2c. Stent Preparation Through Laser Cutting and Crimping

In case the crystallinity of the extruded PLLA tubing is still not highenough for extruded tubing, it can be expanded in a glass mold at about90° C. and then be cut into stent by laser.

Example 3 Multi-Modal PLLA-COOH System and Stent Preparation

3a. Preparation of Multi-Modal PLLA-COOH System

10 g low Mw PLLA-COOH (Mw=50 kg/mol), 200 g medium Mw PLLA-COOH (Mw=200kg/mol) are mixed with 1 kg high Mw PLLA-COOH (Mw=600 kg/mol) through atwin screw compounder at 190° C.

3b. Tubing Extrusion

The multi-modal PLLA-COOH blend tubing is formed through extrusion in asignal or twin screw extruder at 200° C. The size of the extruded tubingis set at 0.02″ for ID and 0.06″ for OD. In case there is no need to useexpander to further increase the crystallinity and biaxial orientation,the size of the extruded tubing can be directly set at 0.12″ for ID and0.13″ for OD.

3c. Stent Preparation Through Laser Cutting and Crimping

The tubing (ID=0.012″ and OD=0.013″) is directly cut into a stent bylaser and crimped to smaller size (0.05″) at which time it is ready touse.

In case the crystallinity and orientation of the extruded tubing needsto be further increased, the tubing will be expanded in a glass mold atabout 90° C. The expanded tubing will be cut into stent by laser.

What is claimed:
 1. A stent, comprising: a blend comprising or formedfrom a high molecular weight polyester and a medium molecular weightpolyester, wherein the high molecular weight polyester has a molecularweight of about 200,000 Da to about 1,000,000 Da; and the mediummolecular weight polyester has a molecular weight of about 20,000 Da toabout 200,000 Da; and wherein the high molecular weight polyester andthe medium molecular weight polyester are independently selected fromthe group consisting of poly(L-lactide),poly(L-lactide-co-ε-caprolactone), poly(D-lactide-co-ε-caprolactone),poly(L-lactide-co-trimethylene carbonate),poly(D-lactide-co-trimethylene carbonate), and combinations thereof;wherein the high molecular weight polyester and the medium molecularweight polyester are different; wherein at least a portion of the mediummolecular weight polyester is substituted with an acidic moiety.
 2. Thestent of claim 1, wherein the medium molecular weight polyester has amolecular weight of about 50,000 Da to about 100,000 Da.
 3. The stent ofclaim 1, wherein the medium molecular weight polyester comprises about2% w/w to about 20% w/w of the blend.
 4. The stent of claim 1, whereinat least about 20% of the medium molecular weight polyester issubstituted with an acidic moiety.
 5. The stent of claim 1, whereinabout 100% of the medium molecular weight polyester is substituted withan acidic moiety.
 6. The stent of claim 1, wherein the acidic moiety isselected from the group consisting of a carboxylic acid, a sulfinicacid, a sulfonic acid and a phosphonic acid.
 7. The stent of claim 6,wherein the acidic moiety is a carboxylic acid.
 8. The stent of claim 1,wherein the high molecular weight polyester is substituted with anacidic moiety.
 9. The stent of claim 1, wherein the high molecularweight polyester has a molecular weight from about 300,000 Da to about700,000 Da.
 10. The stent of claim 1, wherein the blend furthercomprises or is further formed from a low molecular weight polyesterhaving a molecular weight of about 200 Da to about 20,000 Da.
 11. Thestent of claim 10, wherein the low molecular weight polyester issubstituted with an acidic moiety selected from the group consisting ofa carboxylic acid, a sulfinic acid, a sulfonic acid, a phosphonic acidand combinations thereof.
 12. The stent of claim 10, wherein the lowmolecular weight polyester comprises from about 0.2% w/w to about 5% w/wof the blend.
 13. The stent of claim 1, wherein the high molecularweight polyester is independently selected from the group consisting ofpoly(L-lactide-co-ε-caprolactone), poly(D-lactide-co-ε-caprolactone),poly(L-lactide-co-trimethylene carbonate),poly(D-lactide-co-trimethylene carbonate), and combinations thereof. 14.The stent of claim 1, wherein the high molecular weight polyester ispoly(L-lactide).
 15. The stent of claim 10, wherein the high molecularweight polyester and the low molecular weight polyester arepoly(L-lactide).
 16. The stent of claim 1, wherein the stent is avascular stent.
 17. The stent of claim 16, wherein the vascular stentdegrades substantially completely in about 8 to about 24 months.